Lifetime smoking prevalence in Northern Plains American Indians (Al) is above 50%, more than double the rate in the overall U.S. population. More worrisome is that smoking prevalence is actually increasing among some Al youth. Our work demonstrates that Als have a unique pattern of smoking, with Als typically smoking one-half the number of cigarettes per day compared with smokers in the majority culture. We also observed that more recent generations of Als are initiating smoking at younger ages than in past generations. Yet few rigorous scientific studies have examined the genetic and non-genetic influences on patterns of tobacco use in Als. From 2001 to 2007, we conducted the Education and Research Towards Health (EARTH) study, which documented the prevalence of current smoking among Northern Plains' EARTH participants was 43%, compared to only 19% in the Southwest tribe. Although these differences are likely multi-factorial, the reasons for such radically, different smoking prevalences are unknown. To explicate these population-level differences in smoking patterns, we propose to examine the genetic and non-genetic factors associated with cigarette smoking patterns in a stratified random sample of 600 members in the original EARTH cohort. Our overarching hypothesis is that the susceptibility of Als to smoking and nicotine dependence has an underlying genetic component, due to gene variants related to dopamine, serotonin, and nicotine metabolism, as well as psychosocial, environmental, cultural, and contextual influences. Therefore, our specific aims are to: 1) Perform candidate-gene association studies between known smoking-related polymorphisms and smoking status; 2) Determine the association between smoking-related polymorphisms and nicotine dependence among smoker; and 3) Examine whether the pattern of association of specific polymorphisms with smoking status and nicotine dependence varies systematically by tribe. Cigarette smoking is the number 1 cause of preventable death in the U.S.^ The proposed research will illuminate the causes of smoking in 2 culturally distinct Al tribal groups, ultimately to identify targets for intervention at the individual and population levels. By understanding how particular genotypes, in concert with non-genetic factors, predispose some Al tribal groups to smoking, we can begin to affect smoking and the multitude of preventable and costly tobacco-related diseases. Including genetic information is unique in studies of smoking behaviors among Als, and may have a role in shaping smoking prevention and cessation programs at the individual and community level. Given the unique laws governing tobacco sales on tribal lands, our findings could have a myriad of programmatic and policy-related public health impacts.